Infectious bovine rhinotracheitis (IBR) is an acute and contagious infectious bovine disease, often aggravated by bacterial complications (Pastoret P. P., Ann. Med. Vet., 122, 371-391, 1978). This disease occurs, either in a respiratory form (IBR proper), which is predominant and which mainly affects young bovines, or in a genital form, infectious pustular vulvovaginitis (IPV) which has been historically important but which is currently more rare (Yates W. P., Can. J. Comp. Med., 46, 225-263, 1982). IBR is one of the principal causes of respiratory ailments in bovines and causes considerable economic losses both in the dairy industry and in meat production. Given the economic importance of this disease, sanitary barriers aimed at banning the import of infected animals have been introduced by a number of countries.
This disease is of viral nature and its etiological agent has been identified as type 1 bovine herpesvirus (BHV-1) (Madin S. H. et al., Science, 124, 721-722, 1956). This virus is classified in the family Herpesviridae and belongs more specifically to the subfamily Alphaherpesviridae of which the prototype is type 1 human herpes simplex virus (HSV-1) (Armstrong J. A. et al., Virology, 14, 276-285, 1961; Roizman B. et al., Arch. Virol., 123, 425-449, 1992). As most herpesviruses, the BHV-1 virus can be present in the latent state in its host and be reactivated under certain circumstances (stress, transport and the like). The control of this disease is based both on sanitary prophylaxis and on medical prophylaxis.
The clinical diagnosis is rendered difficult in the serious superinfected forms, which show, in this case, similarities with other bovine respiratory infections, and is not always easy to implement. Definite proof of an IBR disease can be provided only with laboratory tests (Gilbert Y. et al., Rev. Med. Vet., 3, 383-389, 1976; Fedida H. and Dannacher G., Bull. Lab. Vet., 5, 35-46, 1982). The isolation of the virus during cell culture from ecouvillonnages produced on the suspected animals remains the best means of diagnosing the disease. But this technique is slow and in particular cumbersome to implement. Consequently, simpler and more rapid techniques based on the detection of the BHV-1 antigens or, increasingly, on the detection of specific antibodies in the serum of the suspected animals, are now preferred in its place. Numerous tests using the ELISA technique are currently on the market (Cheng-Feng Z. and Forbes S. D., New Zealand, Vet. J., 36, 204-205, 1988). Seroneutralization remains, however, the official technique during European or international commercial transactions.
The control of IBR is based mainly on vaccination (Straub O. C. and Mawhinney I. C., Vet. Rec., 122, 407-411, 1988).
Three types of vaccines have been used to protect bovines against IBR (Kit M. et al., European Patent Application No. 0 316 658 A1, 1988).
The vaccines based on attenuated viruses obtained by a large number of successive passages of the pathogenic viruses on cells of bovine origin, by adaptation of these same viruses on cells of an origin other than bovine, or by selection of heat-stable spontaneous viral mutants. These vaccines are easy to produce, of relatively low cost and injectable.
They induce a rapid protection of long duration (Casselberry N. H., J.A.V.M.A., 152, 853-856, 1968). They have, nevertheless, a number of disadvantages since they possess a residual virulence for gestating cows (abortions) and can recover their original virulence by reversion. Furthermore, the possibility of establishment of a latency following their injection cannot be excluded. Heat-sensitive strains have been developed in order to overcome these disadvantages but they require an administration by the intranasal route, which is not very practical (Kahrs R. F. et al., J.A.V.M.A., 163, 437-441, 1973).
The vaccines prepared based on inactivated viruses, obtained by treatment of the pathogenic virus with physical or chemical agents (Durand H. et al, Bull. Soc. Vet. Pr. 65, 193-204, 1981). The manufacture of these vaccines is a lot more expensive since it necessitates numerous controls. These vaccines are also less effective than the attenuated live vaccines and necessitate several successive administrations in the presence of adjuvant in order to induce a good protection.
The viral subunit vaccines are obtained by partial purification of the envelope glycoproteins responsible for the protective immunity (Babiuk L. A. et al., Virology, 159, 57-66, 1987), after culturing the BHV-1 virus. Perfectly innocuous, these vaccines too are of relatively high cost because of the purification step, the need to use an adjuvant and the multiple injections required to induce a protective immune response (Israel B. A. et al., Vaccine 6, 349-356, 1988).
The vaccines commonly used for controlling IBR are therefore far from being satisfactory, either because they possess a residual virulence, or because they are not very practical to use, or finally because they are relatively expensive. On the other hand, the main disadvantage of the three types of vaccines described above is that they do not permit differentiation between infected animals and vaccinated animals, a condition which is absolutely necessary in order to conduct a reasoned prophylaxis, by vaccination and simultaneous elimination of the infected animals, with a view to the eradication of IBR.
Experimental attenuated live vaccinal strains have been proposed as solutions to this problem. They were obtained by genetic recombination by deletion of the gene encoding thymidine kinase (Kit M. et al., European Patent Application No. 0 316 658 A1, 1988). These strains do not, however, make it possible to solve the problem caused by apparently healthy animals, but carriers of the virus in the latent state, which represent a potential reservoir for transmission of the disease. Neither do they permit differentiation between vaccinated animals and infected animals.
Other vaccines based on BHV-1 viruses deleted in the genes encoding thymidine kinase and the glycoprotein gIII (homologous to the glycoprotein gC of HSV-1) have been proposed (Kit M. et al., European Patent Application No. 0 326 127 A2, 1989) in order to differentiate the vaccinated animals from the infected animals. The equivalents of this glycoprotein in the herpesviruses HSV-1 (gC) and PRV (gIII) have proved to be non-essential for viral replication in vitro (Holland T. C. et al., J. Virol., 52, 566-574, 1984; Kit S. et al., Am. J. Vet. Res., 48, 780-793, 1987), but the glycoprotein gIII participates in an important fashion in the induction of neutralizing antibodies in animals immunized with BHV-1 (Collins J. K. et al., J. Virol., 52, 403-409, 1984) which might be responsible for a lower activity of these vaccines in the field.
The impossibility of distinguishing the infected animals from the immunized animals with the current commercial vaccines is the major obstacle to a policy for eradication of the disease in the countries affected. Incidentally, this situation also acts as a brake on international exchanges of animals since many countries demand that the bovines be seronegative with respect to BHV-1 during importations Any reasoned eradication policy involves the combined measures of sanitary prophylaxis (slaughtering) and medical prophylaxis (vaccination) In this perspective, an "ideal" vaccine is that which will make it possible to confer, at the best price, an early, satisfactory and lasting immunity, and which, if it is combined with a screening test which is simple to use, will permit an easy differentiation between vaccinated animals and infected animals.